The gene expression profile of T helper (Th) cells as they transition from naive to effector to memory states reveals limited differences among the resting Th populations. While the generation of memory lymphocytes is an essential process for adaptive immunity, the many steps involved in the progression from naive to memory T cells have only been partially defined. We have identified common and differentially expressed genes in naive, effector, resting effector, and memory cells of Th1 and Th2 lineages. The overall gene expression pattern is dramatically different between effector and naive cells as well as effector and resting effector cells. Few differences have been observed between resting effector and memory cells suggesting that effector expressed genes are associated with the activated state of the effector cells and that resting effector cells have acquired many, if not all, of the characteristics of memory cells. Comparable subsets of Th1 and Th2 lineage have also demonstrated limited differences. Together, we have presented a general analysis of gene expression and identified differentially expressed genes in CD4+ T cells during differentiation. The identification of differentially expressed genes in naive, effector, and memory CD4+ T cells of both Th1 and Th2 lineages provides a starting point for elucidating how the processes of memory T cell formation and maintenance are programmed. A better understanding of these processes is essential for the rational design of vaccines and for the development of strategies for clinical intervention to control autoimmune diseases.